Project Summary/Abstract:The long-term goal of this work is to develop new prostate cancer drugs that overcome the resistance seen with current marketed anti-androgen drugs (androgens are male sex hormones). The specific aim of the proposed work is to identify novel lead compounds that work by a different mechanism than that of current drugs. As with current drugs our molecular target will be the androgen receptor. But unlike current drugs that are competive antagonists of androgens' binding to the androgen receptor, our compounds will interfere with the interaction between the androgen receptor and its co-regulator proteins. To that end, we will integrate virtual (computer) screening methods, cell-based assays and crystal structure determinations to identify lead compounds that can potentially be optimized to produce a drug for the treatment of prostate cancer. Virtual screening, which requires the availability of atomic resolution 3D structures of the target protein, provides a cost effective way to screen millions of compounds to identify just a few to be purchased and tested in a biological or biochemical assay. Our access to such 3D structures of the androgen receptor ligand binding domain makes this work possible. The specific aims of this work are to: 1. Utilize virtual screening methods to screen millions of compound for their proper docking into the androgen receptor co-regulator site, as defined by our atomic resolution 3D structures of the androgen receptor ligand binding domain. 2. Select and purchase a few hundred compounds that are "drug like" and have high potential to be intestinally absorbed. 3. Test these compounds in a cell-based assay for their potential to disrupt transcriptional activation, and select the best compounds. 4. Confirm that the selected compounds bind at the co-regulator site using crystal structure determination of the androgen receptor's ligand binding domain in complex with each selected compound. Accomplishing the specific aims outlined in this proposal will provide the foundation for lead optimization and the potential development of novel prostate cancer drugs. Project Narrative: Prostate cancer, which accounts for 10% of male cancer-related deaths in the US, is the second leading cause of cancer death in American men, exceeded only by lung cancer. Although prostate cancer can be successfully treated with current marketed drugs, most of these drugs become ineffective after only a few years of treatment. Our goal is to develop new prostate cancer drugs that overcome the resistance seen with current marketed drugs. [unreadable] [unreadable] [unreadable]